World Health Organization guidelines for Prevention of HIV infection in infants in resource-limited settings recommend single dose nevirapine (SD-NVP) at onset of labor and to infants at 48-72 hours in addition to zidovudine (ZDV) from 28 weeks'gestation (ZDV28w/SD-NVP), for non immunocompromised women. While this regimen reduces perinatal HIV transmission to [unreadable]2%, post exposure resistance mutations to NVP in mothers and infected children raised concerns regarding future efficacy of Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) based treatments. In industrialized countries similarly low transmission rates are obtained using highly active antiretroviral therapy (HAART) regardless of women's immune status. Such regimens have not been rigorously compared for efficacy and safety with simpler regimens. With the increasing availability of protease inhibitors in resource limited settings and the concerns with use of SD- NVP, we propose to evaluate a simple HAART regimen, ZDV + ritonavir boosted lopinavir (ZDV+LPV/r28w), for prevention of mother to child HIV transmission (PMTCT) in a non-breastfeeding population. The primary objective of this study is to compare the efficacy, long term safety for infants and mothers, and feasibility of ZDV+LPV/r28w versus ZDV28w/SD-NVP for PMTCT. All infants will receive one week ZDV and will be formula fed. Secondary objectives are to: (1) evaluate the mortality, morbidity, CD4 evolution and time to treatment initiation in women up to 24 months after ZDV+LPV/r prophylaxis interruption;(2) assess the incidence of HIV resistance mutations in women after delivery and in HIV infected children;(3) study the pharmacokinetics of LPV/r in Thai pregnant women;and (4) monitor the virological response to ZDV+LPV/r. This multicenter, phase III, randomized, controlled trial will build upon an existing two-arm study, PHPT-5a, with a third arm to be compared with the reference arm (ZQV28w/SD-NVP). The revised study will enroll a total of 2097 consenting HIV-1 infected pregnant women, with CD4 count >250/mm3 (699 per arm including 5% non evaluable;alpha 5%;power: 80%;delta for non-inferiority testing between groups: 1.5%). The primary endpoint is infant HIV status based on confirmed DNA-PCR results at birth, 1, 2, 4 and 6 months. The study represents a collaborative effort of Harvard University, the Institut de Recherche pour le Developpement (France), the Thai Ministry of Public Health, and Mahidol and Chiang Mai Universities, through a network of 45 public hospitals in Thailand. If the simple ZDV+LPV/r28w regimen proves to be efficacious and safe for PMTCT, avoiding risks of resistance mutations to NNRTIs for both mothers and infected children and therefore preserving their future drug options, this study will have important public health imolications for industrialized and developing countries.